Impact of antigenemia on the bioactivity of infused anti-Tac antibody: implications for dose selection in antibody immunotherapies.
In patients with malignancies and immune disorders expressing Tac (alpha chain of the interleukin 2 receptor; CD25), physiologic shedding of this receptor may lead to high blood levels of the soluble form (sTac). This system was used to model the interaction of soluble antigen with antibody in therapeutic settings and to develop rational principles to optimize the delivery of antibody to tumor target cells. First, we confirmed that sTac in vivo can block anti-Tac binding sites and diminish antibody binding to Tac+ cells. Second, the bioactivity of antibody in vivo correlated directly with the amount of antibody infused and inversely with the sTac concentration. Third, bindability of antibody declined in the hours and days after anti-Tac infusion in patients. Finally, tumor targeting was achieved even in the presence of excess sTac, demonstrating a partition of antibody between soluble and cell-bound antigen. A role is proposed for the Brambell receptor (FcRB) to delay saturation of human or chimeric antibodies via differential catabolism of antigen-antibody complexes. Principles are developed for predicting activity of administered antibody in the presence of soluble antigen to assist in dose selection in passive, radioimmuno and immunotoxin therapies.
Junghans
R P
RP
Biotherapeutics Development Lab, Harvard Medical School, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. junghans@warren.med.harvard.edu
Carrasquillo
J A
JA
Waldmann
T A
TA
D001682:Biological Availability; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D015458:Leukemia, T-Cell / Q000628:therapy*; D009182:Mycosis Fungoides / Q000628:therapy*; D016499:Radioimmunotherapy; D015375:Receptors, Interleukin-2 / Q000097:blood / Q000276:immunology*; D012995:Solubility
D015375:Receptors, Interleukin-2